Gene expression leading to the production of protein is most frequently regulated at the level of RNA production, and is termed transcription. Generally, control of transcription is mediated by activator or repressor proteins termed transcription factors. A gene is transcribed after a sequence of events determined by transcription factors has resulted in positioning an enzyme (i.e., RNA polymerase) in the proper location and configuration on the DNA. Transcription factors act through at least two essential mechanisms: (i) binding to specific DNA sequences; or (ii) interacting with other proteins which subsequently influence transcription initiation. The DNA sequences which are involved in regulation of either viral or eukaryotic gene expression and are the targets for transcription factors occur in a variety of locations and at various distances from the transcriptional start and stop sites. These DNA sequences contributing to regulation consist of complex arrays of relatively short DNA sequence motifs. It is believed that tissue specific gene expression occurs as a consequence of cooperation between transcription factors and the DNA sequences to which they bind. Each motif is a binding site for a specific family of transcription factors.
For the CREB family, the consensus binding site has been identified by Montminy et al., 1986 Proc. Natl. Acad. Sci., USA, 83: 6682-6686). This sequence, TGACGTCA, is present in a wide variety of viral and cellular genes, most notably E1A-inducible adenoviral genes and cAMP-inducible cellular genes. Some variation is found in the core sequence with retention of essential function. Specificity of CREB protein binding to particular enhancers can be altered by interaction with viral oncoproteins, including Hepatitis B virus X (Maguire, H. F., et al, 1991, Science 252:842-844), Human T-cell leukemia virus (HTLV-1) tax (Zhao, L. J., et al, 1992, Proc. Natl. Acad. Sci. USA. 89:7070-7074; Armstrong et al., 1993, Proc. Natl. Acad. Sci. USA. 90:7303-7307; Suzuki, et al., 1993, Proc. Natl. Acad. Sci. USA. 90:610-614.; Wagner and Green, 1993, Science 262:395-399).
The CREB/ATF1 family of transcription factors is part of the bZIP superfamily of transcription factors. The most significant structural similarity is the presence of a region with many basic amino acids (b region), and a separate domain that allows close interaction with other proteins with like structure, analogous to a zipper (ZIP). The basic domain has a high concentration of the positively charged amino acids lysine and arginine, which form a tightly coiled alpha helix in the presence of DNA. The basic domain lies in close proximity to a series of amino acids in which leucine is present at every seventh position (the leucine zipper). Further, the leucine zipper forms an amphipathic alpha helix organized into coiled-coils with one surface being hydrophobic and the opposite surface being hydrophilic. This provides for close pairing or dimerization with either identical proteins (homodimers) or similar proteins (heterodimers).
The numbering of the amino acid sequences for ATF1 used in this application is based on the EuGene project designation of the ATF1--Human (fragment) reported in Entry A34223. See also Hal T. et al, Genes Dev. 3:2083-2090 (1989).